Obesity is a life-threatening disorder where there is increased risk of morbidity and mortality, particularly from associated diseases such as hypertension, diabetes mellitus, ischemia, dyslipidemia, coronary heart disease, cancer and gall bladder disease. The economic consequences significantly impact the U.S. health care system, both through direct and indirect (costs associated with morbidity and mortality) medical costs. In 2008 dollars, the costs of medical care of obesity were roughly $147 billion (Finkelstein et al., Health Affairs 2009; 28: w822-2831). Complications from these diseases lead to a decrease in quality of life, excessive burden on health care resources and even death.
Obesity is defined as having a body mass index (BMI) of ≥30 kg/m2 and is calculated as follows: BMI=(mass in kg)÷(height in meters)2. An individual with a BMI between 25 and 29.9 is considered overweight and may also be at risk for the associated diseases and their complications as stated above. There are other measures that are indicative of obesity such as waist circumference, waist-to-height ratio or waist-to-hip ratio (Heitmann, B L, Lissner, L Obesity Reviews. 2011; 12:478-81). Obesity may also be defined based on body fat content which would be >25% for males and >30% for females. Nonetheless, BMI generally has been shown to correlate with morbidity and mortality. As BMI increases there is an increased risk of death from causes that are independent of other risk factors (Flegal, K M, et al. JAMA. 2013; 71:71-82). Research has shown that a modest reduction in BMI can significantly reduce the risk of developing coronary heart disease. The most common diseases associated with obesity are cardiovascular disease, diabetes mellitus, gall bladder disease, and diseases of the reproductive organs.
Consideration of treating a patient for weight loss is not only for the reason of decreasing morbidity and mortality, but also because there is strong data from randomized control trials that weight loss reduces risk factors for additional diseases. Thus, treatment of the overweight and obese conditions will reduce the risk and the consequence of other diseases. The most common diseases associated with obesity are coronary heart disease, diabetes mellitus, cancers (most notably endometrial, breast, and colon), hypertension, dyslipidemia, stroke, liver and gall bladder disease, sleep apnea and respiratory problems, osteoarthritis and diseases of the reproductive organs. Research has shown that a modest reduction in BMI can significantly reduce the risk of developing most of these diseases (Clinical Guidelines on the Identification, Evaluation and Treatment of Overweight and Obesity in Adults: The Evidence Report. NIH Publication No. 98-4083).
Obesity is a growing health care concern in the Western hemisphere and increasingly worldwide. Major countries with rapidly increasing obese populations include the United States, Mexico, India and China. The increased number of obese children and adults is due largely to the increasing availability of and preference for high fat foods. Another important factor has been decreased activity in the daily routine of many people. From 1994 to 2010 there has been an increase in the incidence of obesity in the USA of over 60% such that 35.7% of adults and 17% of children in the United States are now considered obese. From 2002 to 2010, the number of individual states in the USA with obese (BMI≥30) populations of 25% or greater has risen from three to thirty-six (Ogden C L, et al. NCHS data brief, no 82. Hyattsville, Md.: National Center for Health Statistics, 2012).
Despite the magnitude of the problem and the corresponding toll on quality of life and health care costs, there are only limited drug-treatment options currently available (Withrow, D, Alter, D A Obesity Reviews. 2011; 12:131-41). Typically, the first line of treatment a doctor may advise to a patient is a modified diet and lifestyle changes such as reducing overall caloric intake, especially from fats, and increasing physical activity. Unfortunately, many patients find maintaining an adequate level of diet and exercise to be difficult and require additional help from drug therapy to achieve their weight loss recommendation.
Marketed drugs currently available have not been overly successful as treatments for obesity due to either poor efficacy or poorly tolerated side-effect profiles. One of the more efficacious drugs was dexfenfluramine (Redux™) which acted indirectly on the 5-hydroxytryptamine (5-HT) pathway, but reports of cardiac valve defects in up to one third of patients led to its withdrawal by the FDA in 1998. The N-dealkylated metabolite norfenfluramine is a potent agonist of 5-HT2B which is thought to be responsible for the cardiac valve effects (Fitzgerald L W, et al. Mol Pharmacol 2000; 57(1):75-81). Other drugs have been launched in the USA or Europe: orlistat (Xenical™), a drug that prevents absorption of fat by the inhibition of pancreatic lipase, sibutramine (Reductil™), a 5-HT/noradrenaline re-uptake inhibitor and rimonobant (Accomplia™). However, side effects associated with these products have limited their long-term utility. Xenical™ is reported to cause gastrointestinal distress in patients, while rimonobant and sibutramine were removed from the market in 2009 and 2010, respectively, due to intolerable side effects.
Serotonin (5-hydroxytryptamine, 5-HT) mediates a wide range of physiological responses through its seven subfamilies (5-HT1-5-HT7) and at least fourteen receptors (Barnes N M, Sharp T, Neuropharmacology. 1999; 38(8):1083-152; Hoyer D, et al. Pharmacol Biochem Behav. 2002; 71(4):533-54; Kroeze W K, et al. Curr Top Med Chem. 2002; 2(6):507-28). Serotonin receptor modulators have been targeted as therapeutic agents for many years and several marketed drugs target serotonin receptor activities. For example, buspirone used to treat anxiety and depression is a selective 5-HT1A receptor partial agonist; sumatriptan used to treat migraine is a selective 5-HT1B and 5-HT1D receptor agonist and several typical and atypical antipsychotic drugs have inverse agonist activity at 5-HT2A and 5-HT2C receptors (Meltzer H Y, Roth B L. J Clin Invest. 2013 Dec. 2; 123(12):4986-91). In 2012, the FDA approved the use of lorcaserin, a 5-HT2C receptor agonist for the treatment of obesity (Thomsen W J, et al. J Pharmacol Exp Ther. 2008; 325(2):577-87; Martin C K, et al. J Clin Endocrinol Metab. 2011; 96(3):837-45: Smith S R, et al. Obesity (Silver Spring). 2009; 17(3):494-503). Modulation of serotonin receptors has application in abroad range of therapeutic areas.
The 5-HT2 receptor subfamily consists of 5-HT2A, 5-HT2B, and 5-HT2C receptors. They share high homology in their amino acid sequences, couple to the Gq family of G-proteins, and activate phospholipase C (PLC). Activation of 5-HT2 receptors leads to increases in intracellular levels of Ca2+ and phosphoinositol hydrolysis. The 5-HT2C receptor is predominantly expressed in the choroid plexus, cortex, basal ganglia, hippocampus and hypothalamus and has been implicated in appetite regulation, anxiety, depression, schizophrenia, and neuroendocrine regulation (Bickerdike M J. Curr Top Med Chem. 2003; 3(8):885-97; Leysen J E. Curr Drug Targets CNS Neurol Disord. 2004; 3(1):11-26; Serrstti A, et al. Expert Opin Ther Targets. 2004; 8(1):15-23; Higgins G A, et al. Trends Pharmacol Sci. 2013; 34(10):560-70; Wacker D A, Miller K J. Curr Opin Drug Discov Devel. 2008; 11 (4):438-45). In the last ten years, there have been many medicinal chemistry efforts to discover potent and selective 5-HT2C receptor agonists to treat obesity, schizophrenia, and mood disorders [Huck B R, et al. Bioorg Med Chem Lett. 2006; 16(15):4130-4; Huck B R, et al. Bioorg Med Chem Lett. 2006; 16(11):2891-4; Siuciak J A, et al Neuropharmacology. 2007 February; 52(2):279-90; Grauer S M, et al. Psychopharmacology (Berl). 2009 May; 204(1):37-48; Marquis K L, et al. J Pharmacol Exp Ther. 2007 January; 320(1):486-96; Liu K K, et al. Bioorg Med Chem Lett 2010; 20(1):266-71]; Dunlop J. et al. J Pharmacol Exp Ther. 2011 June; 337(3):673-80); Miller K J, Molecular Interventions 2005; 5(5): 282-291. Several compounds have been advanced to human clinical trials, including vabicaserin for schizophrenia, a compound from a company Athersys, ATHX-105, for obesity, and lorcaserin for obesity. Lorcaserin is currently the only 5-HT2C receptor agonist approved by the FDA for the treatment of obesity.
One of the challenges to discover novel selective 5-HT2C receptor agonists is achieving selectivity against 5-HT2A and 5-HT2B receptors due to their high similarities in molecular structure, pharmacology and signaling pathways. The 5-HT2A receptor is widely expressed in the central nervous system (CNS) and peripheral tissues. Activation of the 5-HT2A receptor can result in hallucination (Nichols D E. Pharmacol Ther. 2004; 101 (2):131-81), platelet aggregation, and vascular smooth muscle contraction. The 5-HT2B receptor is expressed in the liver, kidney, lung, heart, pancreas, spleen, brain, spinal cord, gastrointestinal tract, placenta, and coronary and pulmonary arteries. Activation of 5-HT2B receptors has been linked to valvulopathy (Fitzgerald L W, et al. Mol Pharmacol. 2000; 57(1):75-81). Therefore, high selectivity against the 5-HT2C receptor and the 5-HT2B receptor is necessary to minimize the potential side effects of a 5-HT2C receptor agonist especially in the treatment of obesity and other chronic conditions and diseases. The clinical dose of lorcaserin is limited by sub-optimal selectivity over the 5-HT2A receptor. This resulted in unacceptable CNS effects at the higher doses of lorcaserin evaluated in clinical trials. More selective agonists, such as those of the present invention, would be able to achieve greater efficacy of 5-HT2C-mediated diseases through more effective agonism of the 5-HT2C receptor at higher doses that do not agonize the 5-HT2A receptor. In addition to feeding behavior, it is believed that 5-HT2C may play a role in obsessive compulsive disorder, some forms of depression, and epilepsy. Accordingly, 5-HT2C agonists can have anti-panic properties as well as properties useful for the treatment of sexual dysfunction. The potential of 5-HT2C agonists to treat substance abuse is discussed in “From obesity to substance abuse: therapeutic opportunities for 5-HT2C receptor agonists,” Trends in Pharmacol Sci., 2013; 34: 560-570. For example, lorcaserin has been reported to decrease nicotine self-administration in female rats [Levin, E D, et al, J. Pharmacol. Exp. Ther., 338(3), 890-896 (2011)] and in a press release dated Nov. 3, 2014, Eisai and Arena Pharmaceuticals reported results of a Phase 2 trial in humans suggesting that the compound may be useful to aid in tobacco smoking cessation.
In summary, the 5-HT2C receptor is a validated and well-accepted receptor target for the treatment of metabolic and CNS-related disorders, and it can be seen that there is a need in the medical arts for selective 5-HT2C agonists which safely decrease food intake and body weight. The present invention is directed to such compounds which are useful to treat obesity as well as other diseases directly or indirectly associated with 5-HT2C system dysfunction, such as Type 2 diabetes, dyslipidemia, depression, schizophrenia, obsessive-compulsive disorder, drug abuse, sleep disorders, anxiety, epilepsy, tobacco smoking and the maladies that may arise from these diseases. Importantly, the compounds of the present invention are potent 5-HT2c agonists that possess superior selectivity against 5-HT2A and 5-HT2B whose activation has limited the utility of previous 5-HT2C agonists.
U.S. Pat. No. 3,987,047 (Boehringer Ingelheim) discloses tetrahydro-azepinoquinolines with utility as anorectic agents. International patent publications WO 2003/086306 (Arena); WO 2005/000849; WO 2005/003096 (Arena); WO 2006/004931 (Athersys); WO 2006/028961 (Athersys); WO 2006/071740 (Arena); WO 2006/077025 (Roche); WO 2006/117304 (Roche); WO 2007/016029 (Wyeth); WO 2007/030150 (Wyeth); WO 2007/047671 (Wyeth); WO 2007/081299 (Athersys); WO 2007/084622 (Athersys); WO 2007/140213 (Forest); WO 2008/117169 (Pfizer); WO 2008/009125 (Sun Guangri); WO 2010/060952 (Boehringer Ingelheim); WO 2011/111817 (Astellas); as well as U.S. Pat. Nos. 7,514,422; 7,547,699; 7,718,647; 7,893,051; 7,928,099; 7,981,896; 7,981,919; 8,153,621; and 8,232,311 disclose 5-HT2C modulators or compounds that affect food intake. Lorcaserin (Arena) is disclosed in WO 2003/086306 and U.S. Pat. Nos. 6,953,787; 7,514,422; 7,977,329; 8,168,624; and 8,367,657. However, none of the above issued patents or published patent applications discloses the compounds of the present invention.
It is therefore an object of the present invention to provide novel fused tetrahydroazepine compounds which are 5-HT2C receptor agonists and thereby useful to treat obesity, obesity-related disorders, certain psychiatric conditions, and as an aid to tobacco smoking cessation. It is another object of the present invention to provide novel fused tetrahydroazepine compounds which are selective 5-HT2C receptor agonists relative to the 5-HT2A and 5-HT2B receptors. It is another object of the present invention to provide pharmaceutical compositions comprising the 5-HT2C receptor agonists or ligands of the present invention with a pharmaceutically acceptable carrier.
It is another object of the present invention to provide methods for the treatment or prevention of obesity, obesity-related conditions, and certain psychiatric disorders by administering the compounds and pharmaceutical compositions of the present invention to a mammal in need thereof.
It is another object of the present invention to provide methods for aiding tobacco smoking cessation by administering the compounds and pharmaceutical compositions of the present invention to a mammal in need thereof.
It is another object of the present invention to provide methods for the treatment or prevention of disorders, diseases, or conditions responsive to the activation of the 5-HT2C receptor in a mammal in need thereof by administering the compounds and pharmaceutical compositions of the present invention.